Tumor-associated macrophages (TAMs) constitute a major component of the leukocyte infiltrate of most solid tumors, and they usually exhibit a proangiogenic phenotype which facilitates tumor growth in most circumstances. However, the precise mechanisms regulating the proangiogenic properties of TAMs remain largely unclear. In the present study, we found that the expression of hypoxia-inducible factor 2 alpha (HIF-2 alpha) was significantly up-regulated in macrophages from tumor tissues of several solid tumors. Macrophages exposed to tumor cell line derived-culture supernatants (TSN) also expressed high levels of HIF-2 alpha in vitro, without a requirement for hypoxia. We identified miR-17 and miR-20a as the key regulators of HIF-2 alpha expression in TAMs, and autocrine IL-6 played an important role in mediating the expression of miR-17, miR-20a, and thereafter HIF-2 alpha in TAMs. Furthermore, the elevated HIF-2 alpha in TAMs stimulated transcription of a set of proangiogenic genes such as VEGFA and PDGFB, which might in turn contribute to the angiogenic process within tumors. Our data provide evidence in support of the critical role of HIF-2 alpha in the proangiogenic activity of TAMs and also reveal a novel mechanism by which miRNAs regulate TAM functions through modulation of HIF-2 alpha expression under non-hypoxic conditions.